The Hyperthermia-enhanced Association between Tropoelastin and Its 67-kDa Chaperone Results in Better Deposition of Elastic Fibers

The results of our in vitro experiments indicate that exposing cultured human aortic smooth muscle cells and dermal fibroblasts to 39 to 41 °C induces a significant up-regulation in the net deposition of elastic fibers, but not of collagen I or fibronectin, and also decreases the deposition of chondroitin sulfate-containing moieties. We further demonstrate that mild hyperthermia also rectifies the insufficient elastogenesis notable in cultures of fibroblasts derived from the stretch-marked skin of adult patients and in cultures of dermal fibroblasts from children with Costello syndrome, which is characterized by the accumulation of chondroitin 6-sulfate glycosaminoglycans that induce shedding and inactivation of the 67-kDa elastin-binding protein. We have previously established that this protein serves as a reusable chaperone for tropoelastin and that its recycling is essential for the normal deposition of elastic fibers. We now report that hyperthermia not only inhibits deposition of chondroitin 6-sulfate moieties and the consequent preservation of elastin-binding protein molecules but also induces their faster recycling. This, in turn, triggers a more efficient preservation of tropoelastin, enhancement of its secretion and extracellular assembly into elastic fibers. The presented results encourage using mild hyperthermia to restore elastic fiber production in damaged adult skin and to enhance elastogenesis in children with genetic elastinopathies. The results of our in vitro experiments indicate that exposing cultured human aortic smooth muscle cells and dermal fibroblasts to 39 to 41 °C induces a significant up-regulation in the net deposition of elastic fibers, but not of collagen I or fibronectin, and also decreases the deposition of chondroitin sulfate-containing moieties. We further demonstrate that mild hyperthermia also rectifies the insufficient elastogenesis notable in cultures of fibroblasts derived from the stretch-marked skin of adult patients and in cultures of dermal fibroblasts from children with Costello syndrome, which is characterized by the accumulation of chondroitin 6-sulfate glycosaminoglycans that induce shedding and inactivation of the 67-kDa elastin-binding protein. We have previously established that this protein serves as a reusable chaperone for tropoelastin and that its recycling is essential for the normal deposition of elastic fibers. We now report that hyperthermia not only inhibits deposition of chondroitin 6-sulfate moieties and the consequent preservation of elastin-binding protein molecules but also induces their faster recycling. This, in turn, triggers a more efficient preservation of tropoelastin, enhancement of its secretion and extracellular assembly into elastic fibers. The presented results encourage using mild hyperthermia to restore elastic fiber production in damaged adult skin and to enhance elastogenesis in children with genetic elastinopathies. IntroductionElastic fibers constitute the major fibrotic component of the extracellular matrix (ECM) 2The abbreviations used are: ECMextracellular matrixCSCostello syndromeEBPelastin-binding proteinFKBP65FK506-binding proteinSMCssmooth muscle cellsS-Galspliced variant of β-galactosidase. and are responsible for the resilience of blood vessels, lungs, skin, and the connective tissue framework of internal organs. They are composed of a microfibrillar scaffold made up of several glycoproteins and a core consisting of the unique protein polymer elastin. Elastin is formed after the lysyl oxidase-catalyzed cross-linking of multiple precursor molecules (tropoelastin) that are produced and secreted by fibroblasts, chondroblasts, and vascular SMCs (1Vrhovski B. Weiss A.S. Eur. J. Biochem. 1998; 258: 1-18Crossref PubMed Scopus (387) Google Scholar, 2Kielty C.M. Sherratt M.J. Shuttleworth C.A. J. Cell Sci. 2002; 115: 2817-2828Crossref PubMed Google Scholar, 3Mithieux S.M. Weiss A.S. Adv. Protein Chem. 2005; 70: 437-461Crossref PubMed Scopus (382) Google Scholar, 4Wise S.G. Weiss A.S. Int. J. Biochem. Cell Biol. 2009; 41: 494-497Crossref PubMed Scopus (172) Google Scholar, 5Arribas S.M. Hinek A. González M.C. Pharmacol. Ther. 2006; 111: 771-791Crossref PubMed Scopus (191) Google Scholar). Elastogenesis is also modulated by the 67-kDa elastin-binding protein (EBP) (6Hinek A. Wrenn D.S. Mecham R.P. Barondes S.H. Science. 1988; 239: 1539-1541Crossref PubMed Scopus (255) Google Scholar, 7Mecham R.P. Hinek A. Entwistle R. Wrenn D.S. Griffin G.L. Senior R.M. Biochemistry. 1989; 28: 3716-3722Crossref PubMed Scopus (160) Google Scholar), identified as the catalytically inactive spliced variant of β-galactosidase (S-Gal) that has retained the ability to bind to galactosugars and acquired a unique (frameshift encoding) elastin-binding domain (8Hinek A. Rabinovitch M. Keeley F. Okamura-Oho Y. Callahan J. J. Clin. Invest. 1993; 91: 1198-1205Crossref PubMed Scopus (146) Google Scholar, 9Privitera S. Prody C.A. Callahan J.W. Hinek A. J. Biol. Chem. 1998; 273: 6319-6326Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). The 67-kDa S-Gal/EBP serves as a molecular chaperone for intracellular tropoelastin, which binds this highly hydrophobic and unglycosylated protein and escorts it through the secretory pathways, protecting it from premature self-aggregation and proteolytic degradation and assuring its orderly assembly into elastic fibers (10Hinek A. Rabinovitch M. J. Cell Biol. 1994; 126: 563-574Crossref PubMed Scopus (148) Google Scholar). We have described how the coordinated dissociation of tropoelastin from its chaperone and its consecutive assembly into elastic fibers occurs after the binding of S-Gal/EBP to galactosylated components of the microfibrillar scaffold (6Hinek A. Wrenn D.S. Mecham R.P. Barondes S.H. Science. 1988; 239: 1539-1541Crossref PubMed Scopus (255) Google Scholar, 9Privitera S. Prody C.A. Callahan J.W. Hinek A. J. Biol. Chem. 1998; 273: 6319-6326Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 10Hinek A. Rabinovitch M. J. Cell Biol. 1994; 126: 563-574Crossref PubMed Scopus (148) Google Scholar, 11Hinek A. Cell Adhes. Commun. 1994; 2: 185-193Crossref PubMed Scopus (87) Google Scholar). We also found that many S-Gal/EBP molecules (40 to 50%) recycle back to the cell interior following delivery of tropoelastin to the cell surface. These chaperone molecules bind again to their new tropoelastin partners in the recycling endosomes and escort them to the cell surface in consecutive rounds (12Hinek A. Ciba Found. Symp. 1995; 192 (discussion 191–1966): 185-191PubMed Google Scholar, 13Hinek A. Keeley F.W. Callahan J. Exp. Cell Res. 1995; 220: 312-324Crossref PubMed Scopus (55) Google Scholar).Previous studies have documented that either the primary genetic deficiency of the S-Gal/EBP occurring in patients with GM1-gangliosidosis or Morquio B syndrome (14Hinek A. Zhang S. Smith A.C. Callahan J.W. Am. J. Hum. Genet. 2000; 67: 23-36Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 15Morrone A. Bardelli T. Donati M.A. Giorgi M. Di Rocco M. Gatti R. Parini R. Ricci R. Taddeucci G. D'Azzo A. Zammarchi E. Hum. Mutat. 2000; 15: 354-366Crossref PubMed Scopus (55) Google Scholar) or the secondary deficiency of this tropoelastin chaperone, due to the constant shedding induced by its abnormal accumulation of chondroitin 6-sulfate (CS) (16Hinek A. Smith A.C. Cutiongco E.M. Callahan J.W. Gripp K.W. Weksberg R. Am. J. Hum. Genet. 2000; 66: 859-872Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 17Costello J.M. Am. J. Med. Genet. 1996; 62: 199-201Crossref PubMed Scopus (56) Google Scholar, 18Aoki Y. Niihori T. Kawame H. Kurosawa K. Ohashi H. Tanaka Y. Filocamo M. Kato K. Suzuki Y. Kure S. Matsubara Y. Nat. Genet. 2005; 37: 1038-1040Crossref PubMed Scopus (517) Google Scholar, 19Hinek A. Titell M. Schoyer L. Allen W. Gripp K.W. Hamilton R. Weksberg R. Lin A.E. Am. J. Med. Genet. 2005; 133A: 1-12Crossref PubMed Scopus (32) Google Scholar) or dermatan sulfate glycosaminoglycans (Hurler disease) (20Hinek A. Wilson S.E. Am. J. Pathol. 2000; 156: 925-938Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar), consequently prevents the normal assembly of elastic fibers and contributes to the development of the severe clinical phenotypes of these syndromes. Importantly, the genetic manipulations leading to the experimental elimination of proteoglycans rich in chondroitin 6-sulfate and dermatan sulfate (versicans 1 and 2 or biglycan) have also been shown to lead to the rescue of S-Gal/EBP and to the restoration of normal elastogenesis in human and animal cells (21Hinek A. Braun K.R. Liu K. Wang Y. Wight T.N. Am. J. Pathol. 2004; 164: 119-131Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 22Huang R. Merrilees M.J. Braun K. Beaumont B. Lemire J. Clowes A.W. Hinek A. Wight T.N. Circ. Res. 2006; 98: 370-377Crossref PubMed Scopus (74) Google Scholar, 23Merrilees M.J. Ching P.S. Beaumont B. Hinek A. Wight T.N. Black P.N. Resp. Res. 2008; 9: 41-49Crossref PubMed Scopus (78) Google Scholar, 24Hwang J.Y. Johnson P.Y. Braun K.R. Hinek A. Fischer J.W. O'Brien K.D. Starcher B. Clowes A.W. Merrilees M.J. Wight T.N. Am. J. Pathol. 2008; 173: 1919-1928Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar).The results of the present studies involving normal human aortic SMCs and dermal fibroblasts derived from normal human skin, stretch-marked human skin of adult patients, and wrinkled skin of children with CS demonstrate for the first time that exposure to mild hyperthermia (39 to 41 °C) inhibits the deposition of chondroitin sulfate-containing moieties, which are associated with a significant net up-regulation in the deposition of elastic fibers but not collagen I or fibronectin. We then document that, in addition to inhibiting chondroitin 6-sulfate-containing moieties that lead to the preservation of S-Gal/EBP molecules, hyperthermia also induces their faster recycling. This, in turn, triggers a more efficient preservation of newly synthesized tropoelastin, enhancement of its secretion, and extracellular assembly into elastic fibers.DISCUSSIONIt has been well established that exposing mammalian cells to extreme hyperthermia (42 to 43 °C) initiates multiple signaling pathways that can lead either to cell death or extensive aberrations in cell function (37Hildebrandt B. Wust P. Ahlers O. Dieing A. Sreenivasa G. Kerner T. Felix R. Riess H. Crit. Rev. Oncol. Hematol. 2002; 43: 33-56Crossref PubMed Scopus (1314) Google Scholar, 38Corry P.M. Armour E.P. Int. J. Hyperthermia. 2005; 21: 769-778Crossref PubMed Scopus (21) Google Scholar, 39Chang C.K. Chang C.P. Liu S.Y. Lin M.T. Prog. Brain Res. 2007; 162: 525-546Crossref PubMed Scopus (56) Google Scholar, 40Wust P. Nadobny J. Szimtenings M. Stetter E. Gellermann J. Health Phys. 2007; 92: 565-573Crossref PubMed Scopus (17) Google Scholar). It has also been reported that exposing human skin to extreme hyperthermia (43 °C) results in accumulation of amorphous elastin aggregates resembling those observed in photo-aged skin (31Chen Z. Seo J.Y. Kim Y.K. Lee S.R. Kim K.H. Cho K.H. Eun H.C. Chung J.H. J. Invest. Dermatol. 2005; 124: 70-78Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 32Chen Z. Zhuo F.L. Zhang S.J. Tian Y. Tian S. Zhang J.Z. Photodermatol. Photoimmunol. Photomed. 2009; 25: 310-316Crossref PubMed Scopus (14) Google Scholar, 33Cho S. Shin M.H. Kim Y.K. Seo J.E. Lee Y.M. Park C.H. Chung J.H. J. Investig. Dermatol. Symp. Proc. 2009; 14: 15-19Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). In contrast, the results of our study indicate for the first time that exposure to 39 or 41 °C induces significant enhancement in the deposition of elastic fibers in cultures of normal aortic SMCs, as well as in cultures of dermal fibroblasts derived from normal human skin and from patients affected by an acquired idiopathic elastinopathy that has caused stretch marks (26Pieraggi M.T. Julian M. Delmas M. Bouissou H. Virchows Arch. A Pathol. Anat. Histol. 1982; 396: 279-289Crossref PubMed Scopus Google Scholar, F. Hinek A. J. 2005; 25: PubMed Scopus Google Scholar, M.H. J.Y. Clin. Exp. Dermatol. 1994; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar) or the secondary elastinopathy observed in genetic a mild hyperthermia not induce up-regulation in the deposition of or collagen I that the observed enhancement of elastogenesis results from a and not the of and cultures of cell to 41 °C not in the of but a in their not We have previously reported that the addition of elastin to cultures of fibroblasts derived from CS (16Hinek A. Smith A.C. Cutiongco E.M. Callahan J.W. Gripp K.W. Weksberg R. Am. J. Hum. Genet. 2000; 66: 859-872Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar) and syndrome (20Hinek A. Wilson S.E. Am. J. Pathol. 2000; 156: 925-938Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar) their to the that hydrophobic elastin from the We now that the observed in of cells 41 °C not a of but induced by the deposition of elastin the observed in cell and to mild have been to the of F. J. B. PubMed Scopus Google Scholar, J. Cell Sci. 2002; 115: PubMed Google Scholar, S.Y. Cell Sci. 2005; 62: PubMed Scopus Google Scholar, J. M.J. H. R.M. B. Cell 2009; 14: PubMed Scopus Google Scholar) as intracellular of and their and from premature as well as to their the results of our study to demonstrate tropoelastin and the protein a molecular chaperone of collagen Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, K. Cell Biol. 14: PubMed Scopus Google Scholar). the that also tropoelastin, which of and a with collagen from experiments also the of a protein which the of T. Biol. 2000; PubMed Scopus (57) Google Scholar). Importantly, the presented that the up-regulation of elastic fiber deposition can to a more efficient the newly produced tropoelastin and its well established chaperone, has been previously reported that the binding of moieties to the of the S-Gal/EBP induces a in the of this in the of its elastin-binding and as well as consecutive dissociation from the cell A. M. Starcher B. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). It has also been that the accumulation of moieties an extensive shedding of S-Gal/EBP molecules from the cell prevents their recycling to the cell and with the normal assembly of tropoelastin into elastic fibers (12Hinek A. Ciba Found. Symp. 1995; 192 (discussion 191–1966): 185-191PubMed Google Scholar, 13Hinek A. Keeley F.W. Callahan J. Exp. Cell Res. 1995; 220: 312-324Crossref PubMed Scopus (55) Google Scholar, A. Zhang S. Smith A.C. Callahan J.W. Am. J. Hum. Genet. 2000; 67: 23-36Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 15Morrone A. Bardelli T. Donati M.A. Giorgi M. Di Rocco M. Gatti R. Parini R. Ricci R. Taddeucci G. D'Azzo A. Zammarchi E. Hum. Mutat. 2000; 15: 354-366Crossref PubMed Scopus (55) Google Scholar, A. Smith A.C. Cutiongco E.M. Callahan J.W. Gripp K.W. Weksberg R. Am. J. Hum. Genet. 2000; 66: 859-872Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). The accumulation of chondroitin and 1 and which the elimination of the S-Gal/EBP and a consequent of normal has been in the of the of and as well as in the development of (20Hinek A. Wilson S.E. Am. J. Pathol. 2000; 156: 925-938Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, T.N. S. R. R. J. Am. J. Pathol. Google Scholar, T.N. 2008; PubMed Scopus Google Scholar, Y. Wight T.N. K. Res. 2008; PubMed Scopus Google Scholar, K.D. K. Fischer J.W. Johnson P. J.Y. A. Wight T.N. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). has also that the experimental elimination of and 1 deposition normal of S-Gal/EBP and elastogenesis (21Hinek A. Braun K.R. Liu K. Wang Y. Wight T.N. Am. J. Pathol. 2004; 164: 119-131Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 22Huang R. Merrilees M.J. Braun K. Beaumont B. Lemire J. Clowes A.W. Hinek A. Wight T.N. Circ. Res. 2006; 98: 370-377Crossref PubMed Scopus (74) Google Scholar, 23Merrilees M.J. Ching P.S. Beaumont B. Hinek A. Wight T.N. Black P.N. Resp. Res. 2008; 9: 41-49Crossref PubMed Scopus (78) Google Scholar, 24Hwang J.Y. Johnson P.Y. Braun K.R. Hinek A. Fischer J.W. O'Brien K.D. Starcher B. Clowes A.W. Merrilees M.J. Wight T.N. Am. J. Pathol. 2008; 173: 1919-1928Abstract Full Text Full Text PDF PubMed Scopus (33) Google that the cultures of human SMCs and fibroblasts a significant in the deposition of chondroitin moieties A and with the previously of Y. 1993; PubMed Scopus Google Scholar). the of chondroitin sulfate deposition in cells with further the of this We used dermal fibroblasts derived from CS patients, in which elastogenesis is to up-regulation in the deposition of chondroitin 6-sulfate in normal skin and a consequent secondary S-Gal/EBP deficiency (16Hinek A. Smith A.C. Cutiongco E.M. Callahan J.W. Gripp K.W. Weksberg R. Am. J. Hum. Genet. 2000; 66: 859-872Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 19Hinek A. Titell M. Schoyer L. Allen W. Gripp K.W. Hamilton R. Weksberg R. Lin A.E. Am. J. Med. Genet. 2005; 133A: 1-12Crossref PubMed Scopus (32) Google Scholar). Importantly, established that exposing these cells to 41 °C induced a significant in the production of chondroitin moieties and that with a significant in the of intracellular S-Gal/EBP and tropoelastin, as well as with a enhancement of intracellular tropoelastin and its chaperone, S-Gal/EBP and that the of chondroitin 6-sulfate consequently the shedding of S-Gal/EBP reported in this that then initiates a more efficient of S-Gal/EBP molecules to the recycling a for the of the secondary deficiency in this reusable tropoelastin chaperone observed in cells also observed a in the production of and chondroitin in cultures of normal skin fibroblasts and normal aortic SMCs, that the documented is not to CS cells and that it contributes to the rescue of S-Gal/EBP in cell that are to hyperthermia for a the exposure of cell to 41 °C not in the of tropoelastin but enhance the of intracellular tropoelastin, that the up-regulation in the net deposition of elastic fibers is by the of newly synthesized tropoelastin by S-Gal/EBP Importantly, the results of and experiments the of the and a that hyperthermia induced a more efficient secretion of the in cell also documented a faster recycling of S-Gal/EBP in cells 41 °C that this further contributes to the of tropoelastin secretion and to the up-regulation of elastic fiber results of our in vitro those net elastogenesis in cultures to 39 °C for only encourage studies the development of for CS patients, in the normal deposition of elastin has been to a of SMCs (16Hinek A. Smith A.C. Cutiongco E.M. Callahan J.W. Gripp K.W. Weksberg R. Am. J. Hum. Genet. 2000; 66: 859-872Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar) and A. Titell M. Schoyer L. Allen W. Gripp K.W. Hamilton R. Weksberg R. Lin A.E. Am. J. Med. Genet. 2005; 133A: 1-12Crossref PubMed Scopus (32) Google Scholar). the of an elastin present in adult occurs the of and in the S. M.J. J. Dermatol. PubMed Scopus Google Scholar), that a this The of a is also by the A. J. G. 2002; PubMed Scopus (14) Google Scholar) that exposing to a not their the exposure to 41 °C not induce but the deposition of normal elastic fibers in primary cultures of dermal fibroblasts and dermal derived from patients with stretch-marked skin also that the of mild in elastogenesis in and wrinkled IntroductionElastic fibers constitute the major fibrotic component of the extracellular matrix (ECM) 2The abbreviations used are: ECMextracellular matrixCSCostello syndromeEBPelastin-binding proteinFKBP65FK506-binding proteinSMCssmooth muscle cellsS-Galspliced variant of β-galactosidase. and are responsible for the resilience of blood vessels, lungs, skin, and the connective tissue framework of internal organs. They are composed of a microfibrillar scaffold made up of several glycoproteins and a core consisting of the unique protein polymer elastin. Elastin is formed after the lysyl oxidase-catalyzed cross-linking of multiple precursor molecules (tropoelastin) that are produced and secreted by fibroblasts, chondroblasts, and vascular SMCs (1Vrhovski B. Weiss A.S. Eur. J. Biochem. 1998; 258: 1-18Crossref PubMed Scopus (387) Google Scholar, 2Kielty C.M. Sherratt M.J. Shuttleworth C.A. J. Cell Sci. 2002; 115: 2817-2828Crossref PubMed Google Scholar, 3Mithieux S.M. Weiss A.S. Adv. Protein Chem. 2005; 70: 437-461Crossref PubMed Scopus (382) Google Scholar, 4Wise S.G. Weiss A.S. Int. J. Biochem. Cell Biol. 2009; 41: 494-497Crossref PubMed Scopus (172) Google Scholar, 5Arribas S.M. Hinek A. González M.C. Pharmacol. Ther. 2006; 111: 771-791Crossref PubMed Scopus (191) Google Scholar). Elastogenesis is also modulated by the 67-kDa elastin-binding protein (EBP) (6Hinek A. Wrenn D.S. Mecham R.P. Barondes S.H. Science. 1988; 239: 1539-1541Crossref PubMed Scopus (255) Google Scholar, 7Mecham R.P. Hinek A. Entwistle R. Wrenn D.S. Griffin G.L. Senior R.M. Biochemistry. 1989; 28: 3716-3722Crossref PubMed Scopus (160) Google Scholar), identified as the catalytically inactive spliced variant of β-galactosidase (S-Gal) that has retained the ability to bind to galactosugars and acquired a unique (frameshift encoding) elastin-binding domain (8Hinek A. Rabinovitch M. Keeley F. Okamura-Oho Y. Callahan J. J. Clin. Invest. 1993; 91: 1198-1205Crossref PubMed Scopus (146) Google Scholar, 9Privitera S. Prody C.A. Callahan J.W. Hinek A. J. Biol. Chem. 1998; 273: 6319-6326Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). The 67-kDa S-Gal/EBP serves as a molecular chaperone for intracellular tropoelastin, which binds this highly hydrophobic and unglycosylated protein and escorts it through the secretory pathways, protecting it from premature self-aggregation and proteolytic degradation and assuring its orderly assembly into elastic fibers (10Hinek A. Rabinovitch M. J. Cell Biol. 1994; 126: 563-574Crossref PubMed Scopus (148) Google Scholar). We have described how the coordinated dissociation of tropoelastin from its chaperone and its consecutive assembly into elastic fibers occurs after the binding of S-Gal/EBP to galactosylated components of the microfibrillar scaffold (6Hinek A. Wrenn D.S. Mecham R.P. Barondes S.H. Science. 1988; 239: 1539-1541Crossref PubMed Scopus (255) Google Scholar, 9Privitera S. Prody C.A. Callahan J.W. Hinek A. J. Biol. Chem. 1998; 273: 6319-6326Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 10Hinek A. Rabinovitch M. J. Cell Biol. 1994; 126: 563-574Crossref PubMed Scopus (148) Google Scholar, 11Hinek A. Cell Adhes. Commun. 1994; 2: 185-193Crossref PubMed Scopus (87) Google Scholar). We also found that many S-Gal/EBP molecules (40 to 50%) recycle back to the cell interior following delivery of tropoelastin to the cell surface. These chaperone molecules bind again to their new tropoelastin partners in the recycling endosomes and escort them to the cell surface in consecutive rounds (12Hinek A. Ciba Found. Symp. 1995; 192 (discussion 191–1966): 185-191PubMed Google Scholar, 13Hinek A. Keeley F.W. Callahan J. Exp. Cell Res. 1995; 220: 312-324Crossref PubMed Scopus (55) Google Scholar).Previous studies have documented that either the primary genetic deficiency of the S-Gal/EBP occurring in patients with GM1-gangliosidosis or Morquio B syndrome (14Hinek A. Zhang S. Smith A.C. Callahan J.W. Am. J. Hum. Genet. 2000; 67: 23-36Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 15Morrone A. Bardelli T. Donati M.A. Giorgi M. Di Rocco M. Gatti R. Parini R. Ricci R. Taddeucci G. D'Azzo A. Zammarchi E. Hum. Mutat. 2000; 15: 354-366Crossref PubMed Scopus (55) Google Scholar) or the secondary deficiency of this tropoelastin chaperone, due to the constant shedding induced by its abnormal accumulation of chondroitin 6-sulfate (CS) (16Hinek A. Smith A.C. Cutiongco E.M. Callahan J.W. Gripp K.W. Weksberg R. Am. J. Hum. Genet. 2000; 66: 859-872Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 17Costello J.M. Am. J. Med. Genet. 1996; 62: 199-201Crossref PubMed Scopus (56) Google Scholar, 18Aoki Y. Niihori T. Kawame H. Kurosawa K. Ohashi H. Tanaka Y. Filocamo M. Kato K. Suzuki Y. Kure S. Matsubara Y. Nat. Genet. 2005; 37: 1038-1040Crossref PubMed Scopus (517) Google Scholar, 19Hinek A. Titell M. Schoyer L. Allen W. Gripp K.W. Hamilton R. Weksberg R. Lin A.E. Am. J. Med. Genet. 2005; 133A: 1-12Crossref PubMed Scopus (32) Google Scholar) or dermatan sulfate glycosaminoglycans (Hurler disease) (20Hinek A. Wilson S.E. Am. J. Pathol. 2000; 156: 925-938Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar), consequently prevents the normal assembly of elastic fibers and contributes to the development of the severe clinical phenotypes of these syndromes. Importantly, the genetic manipulations leading to the experimental elimination of proteoglycans rich in chondroitin 6-sulfate and dermatan sulfate (versicans 1 and 2 or biglycan) have also been shown to lead to the rescue of S-Gal/EBP and to the restoration of normal elastogenesis in human and animal cells (21Hinek A. Braun K.R. Liu K. Wang Y. Wight T.N. Am. J. Pathol. 2004; 164: 119-131Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 22Huang R. Merrilees M.J. Braun K. Beaumont B. Lemire J. Clowes A.W. Hinek A. Wight T.N. Circ. Res. 2006; 98: 370-377Crossref PubMed Scopus (74) Google Scholar, 23Merrilees M.J. Ching P.S. Beaumont B. Hinek A. Wight T.N. Black P.N. Resp. Res. 2008; 9: 41-49Crossref PubMed Scopus (78) Google Scholar, 24Hwang J.Y. Johnson P.Y. Braun K.R. Hinek A. Fischer J.W. O'Brien K.D. Starcher B. Clowes A.W. Merrilees M.J. Wight T.N. Am. J. Pathol. 2008; 173: 1919-1928Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar).The results of the present studies involving normal human aortic SMCs and dermal fibroblasts derived from normal human skin, stretch-marked human skin of adult patients, and wrinkled skin of children with CS demonstrate for the first time that exposure to mild hyperthermia (39 to 41 °C) inhibits the deposition of chondroitin sulfate-containing moieties, which are associated with a significant net up-regulation in the deposition of elastic fibers but not collagen I or fibronectin. We then document that, in addition to inhibiting chondroitin 6-sulfate-containing moieties that lead to the preservation of S-Gal/EBP molecules, hyperthermia also induces their faster recycling. This, in turn, triggers a more efficient preservation of newly synthesized tropoelastin, enhancement of its secretion, and extracellular assembly into elastic fibers.

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